Retrospective analysis of toxicities and clinical outcomes with BCR-ABL1 tyrosine kinase inhibitors in B-cell acute lymphoblastic leukemia.
Authors: Chad Michael Venn, Kyle Zacholski, Valerie Tran, Yanal Mufeed Alnimer, Thuy Ho, Keri Renee Maher, Ian Michael Bouligny
Journal: Journal of Clinical Oncology (2022)

e19039 Background: The rapid adoption of BCR-ABL1 TKIs in Ph+ B-ALL occurred despite a lack of comparative trials, leading to an absence of data regarding the additive toxicities of BCR-ABL1 TKIs with many standard chemotherapy regimens. BCR-ABL1 TKIs have been associated with severe adverse events and may significantly impact treatment-related morbidity and mortality. The objective of this study is to describe the cumulative toxicity imposed by BCR-ABL1 TKIs and chemotherapy regimens. Methods: A total of 48 patients with Ph+ B-ALL treated with a BCR-ABL1 TKI plus chemotherapy between January 2015 and October 2021 were eligible to assess treatment-related toxicity. High-intensity chemotherapy regimens included HyperCVAD, CALGB 10403, ECOG1910, and ECOG2993; low to moderate intensity regimens included EWALL-Ph-01, TKI + POMP, TKI + corticosteroids, and TKI monotherapy. Regimens containing blinatumomab and inotuzumab ozogamicin in combination with a TKI were assessed separately. The primary outcome was the occurrence of grade 3/4 toxicities, as defined by the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The first occurrence of CTCAE toxicities was collected for each line of therapy patients received. Results: Among the 48 patients analyzed, 71 total lines of therapy were identified. Of these, 54.9% (n = 39) were classified as high-intensity, 29.6% (n = 21) were low-moderate intensity, 9.9% (n = 7) were blinatumomab, and 5.6% (n = 4) were inotuzumab ozogamicin. In high- and low-moderate intensity regimens, a mean of 10.1 and 6.9 grade 3/4 toxicities occurred with dasatinib and imatinib, respectively (p = 0.076). Among low-moderate intensity regimens with dasatinib (n = 11), 63.6% (n = 7) discontinued dasatinib, 9.1% (n = 1) decreased the dasatinib dose, and 36.4% (n = 4) decreased or discontinued dasatinib due to toxicity. High-intensity chemotherapy regimens with dasatinib demonstrated 51.6% (n = 16) discontinuation, 38.7% (n = 12) dasatinib dose reduction, and 62.1% (n = 18) decreased or discontinued dasatinib due to toxicity. Conversely, among low-moderate (n = 4) and high-intensity (n = 5) regimens in combination with imatinib, no discontinuations or dose reductions occurred. These data demonstrate a greater dose reduction and discontinuation rate with dasatinib compared to imatinib in high-intensity regimens (p = 0.011); differences in low-moderate intensity regimens were not observed (p = 0.174). A secondary analysis did not reveal an association with dasatinib discontinuation rate and CR rate (p = 0.829) or overall survival (p = 0.941). Conclusions: A greater incidence of grade 3/4 toxicity leading to dose changes or discontinuation occurred with dasatinib compared to imatinib. While differences in CR or OS due to TKI-related toxicity were not identified, their occurrence likely contributes to treatment-related morbidity.